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With any aging population comes the manifestation of skin that includes, in addition to wrinkles, hyperpigmentation. Along with this, consider an increased incidence of adult acne often leading to postinflammatory hyperpigmentation and the newest baby boom, which accounts for more melasma among women, and the result is an increased demand for skin-lightening products in the United States.

For many years, hydroquinone has been considered one of the most effective skin-lightening agents for treatment of sun-induced pigmentation, postinflammatory hyperpigmentation, melasma and other forms of hyperpigmentation often associated with aging skin. In the U.S., hydroquinone is classified as an over-the-counter (OTC) drug that may be used in concentrations of up to 2%. Most prescription-strength hydroquinone formulations contain 3–4%, but concentrations as high as 10% may be available through compounding pharmacies. When prescribed by a physician, it is often combined with other actives, such as tretinoin, retinol, vitamin C or glycolic acid.

How Does Hydroquinone Work?

There are various theories about how hydroquinone works to affect hyperpigmentation. Some researchers claim that it denatures the melanin-protein complex, causing a decoloration of the skin. Others claim it inhibits the tyrosinase enzyme, as well as the synthesis of the protein associated with melanin. Because of its cytotoxic impact on the melanocyte, it is said to disrupt basic cellular processes, including DNA and RNA synthesis.1–4 Regardless of the mechanism used to lighten skin, the focus these days should really be on the more important concerns regarding the safety of hydroquinone.

Is it Safe?

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There is no doubt about it, hydroquinone is an effective pigment-lightener; however, much attention is now focused on its safety. Not only is safety an issue, but concerns also stem from its designation as “an extreme sensitizer;”5 many individuals are allergic to hydroquinone, and others experience serious contact dermatitis with repeated use—leading, unfortunately, to a prescription for a steroid cream to counter the associated irritation. In extreme cases, a condition known as onchronosis can occur, resulting in blue-black macules or hyperpigmentation accompanied by acne-like lesions. Onchronosis generally requires higher concentrations of hydroquinone and is more prevalent in darker skin. However, lower concentrations may also illicit a poor response, too, which has led many dermatologists to a prescriptive cycling of hydroquinone involving using hydroquinone-containing products for four months, stopping for four months and resuming again for four months, and so on. During the off months, a hydroquinone-free brightener is recommended. At the other end of the spectrum are concerns that hydroquinone causes hypopigmentation, or white spots. This is more prevalent in olive complexions.

Being a metabolite of benzene, hydroquinone has potential mutagenic properties. The Occupational Safety and Health Administration (OSHA) in the U.S. claims “hydroquinone is mutagenic and has cancer-causing potential.” In 1994, the Journal of the American College of Toxicology (now known as the International Journal of Toxicology) published “The Addendum to the Final Report on the Safety Assessment of Hydroquinone.” Its conclusion stated that “hydroquinone is a potent cytotoxic agent that causes mutations and alterations to DNA, and that it should not be used in any leave-on type of product; it is safe for rinse-off products when used in concentrations less than 1%.” When this was published, many cosmetic manufacturers opted to discontinue their hydroquinone lighteners, and some countries went so far as to ban hydroquinone from skin-whiteners. For example, hydroquinone is strictly regulated in many African and Asian countries, and its use is prohibited in the European Union (EU) and Japan. However, many hydroquinone-containing whiteners remain on the market to this day. As a matter of fact, most skin-whitening serums and creams currently available contain 2% hydroquinone.

For whatever reason, hydroquinone still remains the only ingredient recognized as a “lightening agent” by the U.S. Food and Drug Administration (FDA), and its use falls under the regulations as stated in the monograph on skin lightening, which designates hydroquinone as the sole acceptable lightening agent. This means that the use of other ingredients for treating hyperpigmentation cannot be called skin-lighteners or whiteners, so the industry has coined the term “brightener” for these nonhydroquinone alternatives. As recently as 2007, the FDA reported its intent toward banning the use of hydroquinone in nonprescription products due to safety issues, but as of yet has not implemented any new regulations. The Cosmetic Ingredient Review (CIR) Board has agreed to revisit the safety of hydroquinone and report back by March 2009. Perhaps the FDA is awaiting the new report before passing any new regulations or amending the monograph on lightening.

Alternatives to Hydroquinone

Most of the safe alternatives to hydroquinone impact the key enzyme, tyrosinase, that mediates two key steps in melanogenesis. See Key Steps in Melanin Biosynthesis.

Key ingredients. There are several ingredients that inhibit the tyrosinase enzyme, as well as compete with the enzyme’s substrate, L-3,4-dihydroxyphenylalanine (L-DOPA). Botanical extracts, such as Ferula foetida (giant fennel), bearberry, licorice, Sophora angustifolia, kiwi fruit, nasturtium, rumex (yellow dock), Phyllanthus emblica fruit and mulberry contain bioflavonoid components similar in chemical structure to L-DOPA, the end product of Step 1, illustrated in Key Steps in Melanin Biosynthesis. The bioflavonoids compete with the substrate L-DOPA, thereby preventing Step 2, also illustrated in the diagram, from occurring.

Hydroxy acids. Although the use of hydroxy acids—lactic acid, glycolic acid and salicylic acid—in skin-brightening products has generally been utilized to accelerate desquamation and removal of melanin-containing corneocytes, it has recently been shown that a 5% concentration of lactic acid will inhibit the formation of the tyrosinase enzyme, thereby slowing the process of melanin synthesis. Other exfoliating agents used in brightening products include pumpkin enzyme, sutilains (a protease enzyme), lactobacillus ferment and galactoarabian, a molecule that stimulates natural desquamation in the skin.

Controlling inflammation. Controlling inflammation is another strategy for treating hyperpigmentation. The use of anti-inflammatory agents—such as white tea, licorice and green tea—help address the connection between inflammation and pigment formation. These extracts also may act as antioxidants, slowing many of the oxidation steps involved in melanin formation.

Melanin formation. Of particular interest are ingredients that impact melanin formation in multiple ways. An example is zinc glycinate, which stimulates synthesis of an antioxidant protein called metallothionein that binds the copper and reduces tyrosinase synthesis and activity; in addition, it suppresses melanocyte growth factors that stimulate melanin synthesis. Niacinamide has been shown to stop the transfer of melanosomes to neighboring keratinocytes. Glucosamine and dithiooctanediol stop the activation of the tyrosinase enzyme, a step that involves glycosylation, or the addition of a sugar molecule to the inactive proenzyme structure, converting it to the activated enzyme. Obviously, if the enzyme remains inactive, melanin formation ceases.

New studies indicate that melanin formation can also be controlled by affecting the signaling process involved in melanin biosynthesis. Sunscreens and anti-inflammatory agents work by turning off the messengers that signal melanin synthesis to commence. A brown seaweed called Ascophyllum nodosum has been shown to inhibit endothelin-1 (ET-1), a molecule synthesized and released from the keratinocytes after UV exposure. ET-1 stimulates the melanocyte and triggers tyrosinase activity. When the signal molecule ET-1 is inhibited, melanin formation is likewise inhibited. In a similar role, the use of Palmaria palmata, a red algae, has been shown to inhibit the release of stem cell factor (SCF), another signaling molecule released by keratinocytes upon exposure to UVB radiation; SCF activates the melanocyte to make melanin. Palmaria palmata inhibits the release of SCF and therefore inhibits melanocyte activation.

In the past decade, ascorbic acid (vitamin C) has been used to control melanin synthesis. Newer stabilized derivatives of vitamin C include magnesium ascorbyl phosphate (MAP), ascorbyl glucoside and tetrahexyldecyl ascorbate. These derivatives scavenge free radicals that cause erratic melanocyte activity, as well as act as antioxidants inhibiting oxidation steps along the biosynthetic pathway of melanin. They have also been shown to inhibit tyrosinase synthesis and activity.

Finally, the newest and perhaps most exciting agents to fight melanin formation are the peptides. Oligopeptide-34 is a state-of-the-art synthesized peptide that has been shown to decrease alpha-MSH activity and inhibit tyrosinase activity. Although the mechanism is not clearly understood, results indicate that it brightens skin, especially sun-induced hyperpigmentation, in half the time when compared to other brightening complexes. The use of peptides, such as oligopeptide-34 to control pigmentation, may very well be the newest and most effective approach to treating hyperpigmentation. And if safety studies are a good indicator, they are a lot safer for the end user.

The Future

Dealing with issues of pigmentation will undoubtedly continue to be a focus in the skin care arena, and there is certainly no shortage of products designed to address these issues. But the most important question is: Which are effective and safe to use? Although hydroquinone continues to be the only authorized OTC whitening agent in the U.S., there are numerous studies that question its safety, which accounts for its being banned in most countries throughout the world. The pressure remains on pharmaceutical houses, cosmetic companies and raw material suppliers to find safe and legal alternatives to hydroquinone. This past decade has seen a myriad of new brightening agents, all promising to reduce hyperpigmentation while enhancing skin luminosity and, although most have fallen short of hydroquinone’s ability to whiten skin, new cocktails of brighteners are now available that are close in performance and a lot safer to use.

Diana l. Howard, PHD is vice president of technical development for The International Dermal Institute and Dermalogica. She earned her doctorate from the University of California, Los Angeles, where she specialized in plant biochemistry, and has applied her research on skin and the development of novel ingredient complexes in work for major cosmetic companies for more than 24 years.